Pharmacological properties are often dependent on a particular stereochemistry and thus the resolution of a racemic mixture is a useful chemical process.
Ibuprofen, a well know analgesic, is a racemic mixture of carboxylic acids of formula (I): ##STR1## However, although ibuprofen is marketed as the racemic mixture, the (S)-enantiomer is known to be the active agent. If (S)-ibuprofen is to be sold commercially there exists a need for an efficient preferential resolution of racemic ibuprofen. Furthermore it would be desirable for the resolution process to lead directly to an amino acid salt of (S)-ibuprofen since such salts are more soluble and thus may offer pharmaceutical advantages over the carboxylic acid.
There are two classical routes to the resolution of racemic mixtures such as (R)(S)-ibuprofen.
The first requires finding a chiral amine which, when reacted with the (R)(S)-ibuprofen, will form diastereomeric salts the solubilities of which are so different from each other that the diastereomers may be separated, one from the other, by simple crystallization.
The above procedure has two disadvantages: chiral amines, such as (S)-alpha-methylbenzylamine, are expensive reagents, and the product of the separation is not (S)-ibuprofen, but its amine salt. Thus the separation process must be supplemented with procedures to free the (S)-ibuprofen from its amine salt, recover the chiral amine, and, if desired, convert the (S)-ibuprofen to a preferred salt such as an amino acid salt.
The second classical resolution route is preferential crystallization. However, (R)(S)-ibuprofen as such cannot be resolved by preferential crystallization, or any other crystallization technique, because as a crystalline material it takes the form of a racemic compound rather than a mixture of crystals of (R)-ibuprofen and crystals of (S)-ibuprofen. Thus, to use preferential crystallization requires finding a derivative of ibuprofen which does not crystallize in the form of a racemic compound. Non-chiral amines, such as tert-butylamine and diethylamine are suitable for this purpose. However, except for amine costs, preferential crystallization via these amine salts shares the disadvantages cited for the chiral amine route described above.